{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T02:38:48Z","timestamp":1785551928532,"version":"3.56.0"},"reference-count":34,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T00:00:00Z","timestamp":1696118400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T00:00:00Z","timestamp":1696118400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T00:00:00Z","timestamp":1696118400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T00:00:00Z","timestamp":1696118400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T00:00:00Z","timestamp":1696118400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T00:00:00Z","timestamp":1696118400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T00:00:00Z","timestamp":1696118400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Medicinal Chemistry"],"published-print":{"date-parts":[[2023,10]]},"DOI":"10.1016\/j.ejmech.2023.115605","type":"journal-article","created":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T12:50:35Z","timestamp":1687956635000},"page":"115605","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":9,"special_numbering":"C","title":["Discovery of novel diarypyrimidine derivatives bearing six-membered non-aromatic heterocycles as potent HIV-1 NNRTIs with improved anti-resistance and drug-like profiles"],"prefix":"10.1016","volume":"258","author":[{"given":"Xiangyi","family":"Jiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boshi","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waleed A.","family":"Zalloum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chin-Ho","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangkai","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaojiao","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghui","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongwei","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"De Clercq","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Pannecouque","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7168-613X","authenticated-orcid":false,"given":"Peng","family":"Zhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.ejmech.2023.115605_bib1","series-title":"StatPearls, StatPearls Publishing Copyright \u00a9 2022","article-title":"Acquired immune deficiency syndrome","author":"Waymack","year":"2022"},{"key":"10.1016\/j.ejmech.2023.115605_bib2","doi-asserted-by":"crossref","first-page":"5975","DOI":"10.1002\/jmv.28064","article-title":"Discovery of novel 1,2,4-triazole phenylalanine derivatives targeting an unexplored region within the interprotomer pocket of the HIV capsid protein","volume":"94","author":"Jiang","year":"2022","journal-title":"J. Med. Virol."},{"key":"10.1016\/j.ejmech.2023.115605_bib3","doi-asserted-by":"crossref","first-page":"7322","DOI":"10.1021\/acs.jmedchem.9b00175","article-title":"Fifty years in search of selective antiviral drugs","volume":"62","author":"De Clercq","year":"2019","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2023.115605_bib4","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1016\/j.apsb.2019.11.010","article-title":"Development of non-nucleoside reverse transcriptase inhibitors (NNRTIs): our past twenty years","volume":"10","author":"Zhuang","year":"2020","journal-title":"Acta Pharmacol. Sin. B"},{"key":"10.1016\/j.ejmech.2023.115605_bib5","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/j.apsb.2019.08.013","article-title":"Exploring the hydrophobic channel of NNIBP leads to the discovery of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives as potent HIV-1 NNRTIs","volume":"10","author":"Kang","year":"2020","journal-title":"Acta Pharmacol. Sin. B"},{"key":"10.1016\/j.ejmech.2023.115605_bib6","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1128\/CMR.00102-15","article-title":"Approved antiviral drugs over the past 50 years","volume":"29","author":"De Clercq","year":"2016","journal-title":"Clin. Microbiol. Rev."},{"key":"10.1016\/j.ejmech.2023.115605_bib7","doi-asserted-by":"crossref","first-page":"4851","DOI":"10.1021\/acs.jmedchem.8b00843","article-title":"The journey of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) from lab to clinic","volume":"62","author":"Namasivayam","year":"2019","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2023.115605_bib8","doi-asserted-by":"crossref","DOI":"10.1038\/s42004-019-0174-8","article-title":"Discovery of piperidine-substituted thiazolo[5,4-d] pyrimidine derivatives as potent and orally bioavailable HIV-1 non-nucleoside reverse transcriptase inhibitors","volume":"2","author":"Kang","year":"2019","journal-title":"Commun Chem"},{"key":"10.1016\/j.ejmech.2023.115605_bib9","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1056\/NEJMp1710608","article-title":"HIV drug resistance - an emerging threat to epidemic control","volume":"377","author":"Beyrer","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"10.1016\/j.ejmech.2023.115605_bib10","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1128\/AAC.04201-14","article-title":"In vitro resistance selection with doravirine (MK-1439), a novel nonnucleoside reverse transcriptase inhibitor with distinct mutation development pathways","volume":"59","author":"Feng","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"10.1016\/j.ejmech.2023.115605_bib11","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1080\/17425255.2019.1673367","article-title":"Current and emerging non-nucleoside reverse transcriptase inhibitors (NNRTIs) for HIV-1 treatment","volume":"15","author":"Wang","year":"2019","journal-title":"Expert Opin Drug Met"},{"key":"10.1016\/j.ejmech.2023.115605_bib12","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1517\/13543776.2016.1113256","article-title":"Novel diarylpyrimidines and diaryltriazines as potent HIV-1 NNRTIs with dramatically improved solubility: a patent evaluation of US20140378443A1","volume":"26","author":"Huang","year":"2016","journal-title":"Expert Opin. Ther. Pat."},{"key":"10.1016\/j.ejmech.2023.115605_bib13","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2020.112811","article-title":"Targeting dual tolerant regions of binding pocket: discovery of novel morpholine-substituted diarylpyrimidines as potent HIV-1 NNRTIs with significantly improved water solubility","volume":"206","author":"Wang","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2023.115605_bib14","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.antiviral.2009.09.008","article-title":"Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: a review of the last 20 years (1989-2009)","volume":"85","author":"de Bethune","year":"2010","journal-title":"Antivir. Res."},{"key":"10.1016\/j.ejmech.2023.115605_bib15","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1080\/17425255.2019.1604685","article-title":"Pharmacokinetics and pharmacodynamics of cytochrome P450 inhibitors for HIV treatment","volume":"15","author":"Gong","year":"2019","journal-title":"Expert Opin Drug Met"},{"key":"10.1016\/j.ejmech.2023.115605_bib16","doi-asserted-by":"crossref","first-page":"13658","DOI":"10.1021\/acs.jmedchem.1c01015","article-title":"Discovery of novel dihydrothiopyrano[4,3-d]pyrimidine derivatives as potent HIV-1 NNRTIs with significantly reduced hERG inhibitory activity and improved resistance profiles","volume":"64","author":"Wang","year":"2021","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2023.115605_bib17","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.ejmech.2016.05.054","article-title":"Structural optimization of pyridine-type DAPY derivatives to exploit the tolerant regions of the NNRTI binding pocket","volume":"121","author":"Chen","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2023.115605_bib18","doi-asserted-by":"crossref","first-page":"4295","DOI":"10.1021\/jm1002233","article-title":"Crystal structures of HIV-1 reverse transcriptase with etravirine (TMC125) and rilpivirine (TMC278): implications for drug design","volume":"53","author":"Lansdon","year":"2010","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2023.115605_bib19","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1016\/j.cclet.2020.03.028","article-title":"New techniques and strategies in drug discovery","volume":"31","author":"Du","year":"2020","journal-title":"Chin. Chem. Lett."},{"key":"10.1016\/j.ejmech.2023.115605_bib20","doi-asserted-by":"crossref","first-page":"2194","DOI":"10.1002\/med.21581","article-title":"Molecular design opportunities presented by solvent-exposed regions of target proteins","volume":"39","author":"Jiang","year":"2019","journal-title":"Med. Res. Rev."},{"key":"10.1016\/j.ejmech.2023.115605_bib21","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1021\/acs.jmedchem.8b01729","volume":"62","author":"Huang","year":"2019","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2023.115605_bib22","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2020.113051","article-title":"Exploiting the tolerant region I of the non-nucleoside reverse transcriptase inhibitor (NNRTI) binding pocket. Part 2: discovery of diarylpyrimidine derivatives as potent HIV-1 NNRTIs with high Fsp(3) values and favorable drug-like properties","volume":"213","author":"Jiang","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2023.115605_bib23","doi-asserted-by":"crossref","first-page":"2533","DOI":"10.1021\/acs.jpclett.2c00435","article-title":"Long-lived triplet charge separated state and thermally activated delayed fluorescence in a compact orthogonal anthraquinone-phenothiazine electron donor-acceptor dyad","volume":"13","author":"Zhao","year":"2022","journal-title":"J. Phys. Chem. Lett."},{"key":"10.1016\/j.ejmech.2023.115605_bib24","doi-asserted-by":"crossref","first-page":"2729","DOI":"10.1002\/adsc.202200428","article-title":"Palladium-catalyzed domino cyclization\/direct aminosulfonylation between aryl iodides and amines via the insertion of sulfur dioxide","volume":"364","author":"Lv","year":"2022","journal-title":"Adv. Synth. Catal."},{"key":"10.1016\/j.ejmech.2023.115605_bib25","doi-asserted-by":"crossref","first-page":"28961","DOI":"10.1039\/C9RA05869A","article-title":"Discovery of novel 1,4-disubstituted 1,2,3-triazole phenylalanine derivatives as HIV-1 capsid inhibitors","volume":"9","author":"Jiang","year":"2019","journal-title":"RSC Adv."},{"key":"10.1016\/j.ejmech.2023.115605_bib26","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/nprot.2007.517","article-title":"Tetrazolium-based colorimetric assay for the detection of HIV replication inhibitors: revisited 20 years later","volume":"3","author":"Pannecouque","year":"2008","journal-title":"Nat. Protoc."},{"key":"10.1016\/j.ejmech.2023.115605_bib27","doi-asserted-by":"crossref","first-page":"D437","DOI":"10.1093\/nar\/gkaa1038","article-title":"RCSB Protein Data Bank: powerful new tools for exploring 3D structures of biological macromolecules for basic and applied research and education in fundamental biology, biomedicine, biotechnology, bioengineering and energy sciences","volume":"49","author":"Burley","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.ejmech.2023.115605_bib28","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.36340","article-title":"Structural basis for potent and broad inhibition of HIV-1 RT by thiophene[3,2-d] pyrimidine non-nucleoside inhibitors","volume":"7","author":"Yang","year":"2018","journal-title":"Elife"},{"key":"10.1016\/j.ejmech.2023.115605_bib29","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1021\/acs.jpca.9b10726","article-title":"Weak intermolecular CH\u00b7\u00b7\u00b7N hydrogen bonding: determination of (13)CH-(15)N hydrogen-bond mediated J couplings by solid-state NMR spectroscopy and first-principles calculations","volume":"124","author":"Webber","year":"2020","journal-title":"J. Phys. Chem. A"},{"key":"10.1016\/j.ejmech.2023.115605_bib30","doi-asserted-by":"crossref","first-page":"41576","DOI":"10.1074\/jbc.R112.418574","article-title":"Carbon-oxygen hydrogen bonding in biological structure and function","volume":"287","author":"Horowitz","year":"2012","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.ejmech.2023.115605_bib31","doi-asserted-by":"crossref","first-page":"3314","DOI":"10.1021\/ct300418h","article-title":"MMPBSA.py: an efficient program for end-state free energy calculations","volume":"8","author":"Miller","year":"2012","journal-title":"J. Chem. Theor. Comput."},{"key":"10.1016\/j.ejmech.2023.115605_bib32","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1016\/j.drudis.2020.07.017","article-title":"Fsp(3): a new parameter for drug-likeness","volume":"25","author":"Wei","year":"2020","journal-title":"Drug Discov. Today"},{"key":"10.1016\/j.ejmech.2023.115605_bib33","doi-asserted-by":"crossref","first-page":"6752","DOI":"10.1021\/jm901241e","article-title":"Escape from flatland: increasing saturation as an approach to improving clinical success","volume":"52","author":"Lovering","year":"2009","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.ejmech.2023.115605_bib34","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1002\/jps.22242","article-title":"Physicochemical properties of the amorphous drug, cast films, and spray dried powders to predict formulation probability of success for solid dispersions: etravirine","volume":"100","author":"Weuts","year":"2011","journal-title":"J. Pharmaceut. Sci."}],"container-title":["European Journal of Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0223523423005718?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0223523423005718?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T14:58:34Z","timestamp":1759330714000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0223523423005718"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10]]},"references-count":34,"alternative-id":["S0223523423005718"],"URL":"https:\/\/doi.org\/10.1016\/j.ejmech.2023.115605","relation":{},"ISSN":["0223-5234"],"issn-type":[{"value":"0223-5234","type":"print"}],"subject":[],"published":{"date-parts":[[2023,10]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Discovery of novel diarypyrimidine derivatives bearing six-membered non-aromatic heterocycles as potent HIV-1 NNRTIs with improved anti-resistance and drug-like profiles","name":"articletitle","label":"Article Title"},{"value":"European Journal of Medicinal Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ejmech.2023.115605","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2023 Published by Elsevier Masson SAS.","name":"copyright","label":"Copyright"}],"article-number":"115605"}}